rs116719245

Variant names:

• chr2-219281737-C-T
• rs116719245
• NM_006736.6:c.195C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006736.6(DNAJB2):​c.195C>T​(p.Tyr65Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,613,964 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: DNAJB2 NM_006736.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.799
• Publications: 2 publications found

Genes affected

DNAJB2 (HGNC:5228): (DnaJ heat shock protein family (Hsp40) member B2) This gene is almost exclusively expressed in the brain, mainly in the neuronal layers. It encodes a protein that shows sequence similarity to bacterial DnaJ protein and the yeast homologs. In bacteria, this protein is implicated in protein folding and protein complex dissociation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2011]

DNAJB2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2T

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• neuronopathy, distal hereditary motor, autosomal recessive 5

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-219281737-C-T is Benign according to our data. Variant chr2-219281737-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 377779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.799 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (174/152218) while in subpopulation NFE AF = 0.00232 (158/68016). AF 95% confidence interval is 0.00203. There are 2 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006736.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB2	NM_006736.6	MANE Select	c.195C>T	p.Tyr65Tyr	synonymous	Exon 4 of 9	NP_006727.2
	DNAJB2	NM_001039550.2		c.195C>T	p.Tyr65Tyr	synonymous	Exon 4 of 10	NP_001034639.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB2	ENST00000336576.10	TSL:1 MANE Select	c.195C>T	p.Tyr65Tyr	synonymous	Exon 4 of 9	ENSP00000338019.5
	DNAJB2	ENST00000933785.1		c.195C>T	p.Tyr65Tyr	synonymous	Exon 4 of 9	ENSP00000603844.1
	DNAJB2	ENST00000392086.8	TSL:2	c.195C>T	p.Tyr65Tyr	synonymous	Exon 4 of 10	ENSP00000375936.4

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152100 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000907 AC: 228 AN: 251256 AF XY: 0.000891

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00155 AC: 2259 AN: 1461746 Hom.: 6 Cov.: 33 AF XY: 0.00150 AC XY: 1092 AN XY: 727166

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000938 AC: 5 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00194 AC: 2152 AN: 1112006

Other (OTH) AF: 0.00103 AC: 62 AN: 60390

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152218 Hom.: 2 Cov.: 32 AF XY: 0.000914 AC XY: 68 AN XY: 74416

African (AFR) AF: 0.000217 AC: 9 AN: 41516

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00232 AC: 158 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00109

EpiCase AF: 0.00207

EpiControl AF: 0.00202

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Neuronopathy, distal hereditary motor, autosomal recessive 5 (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	DNAJB2-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.5
DANN	Benign	0.79
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116719245; hg19: chr2-220146459;